DESCRIPTION: Applicant's Abstract Use of crack cocaine, which has increased recently among teenagers in the U.S. has been linked both to acute lung injury ("crack lung") and to HIV infection. Findings from the current project have revealed acute cocaine-induced neutrophil activation, suggesting a possible mechanism for crack lung syndrome. In addition, alveolar macrophages (Ams) obtained from habitual crack users, and thus chronically exposed to cocaine in vivo, as well as peripheral blood lymphocytes (PBLs) acutely exposed to cocaine in vitro, exhibited impaired immune function, including markedly reduced ability of Ams to kill infectious microorganisms and tumor cell targets and profound alterations in production of immunoregulatory cytokines by PBLs. These findings suggest that crack use may predispose the user to both inflammatory lung disorders and to opportunistic infection, especially in HIV-positive persons. Our current objective is to evaluate the effects of cocaine on (1) airway and lung injury; (2) regulation of pulmonary and systemic immune effector cells and their ability to respond to lung cancer and (3) susceptibility of these cells to HIV infection and combined impact of cocaine and HIV infection on their response to opportunistic pathogens. Three specific aims will be pursued: 1) we will determine the potential for cocaine to produce airway and lung injury by examining the chronic effects of habitual crack use, as well acute effects of experimental cocaine smoking, on the accumulation and activation of inflammatory cells in the lungs. 2) We will determine the role of cocaine in the regulation of lymphocyte-dependent immune responses, including the modulation of Type 1/Type 2 cytokine balance, molecular pathways of lymphocyte production of TGF-b and the in vivo consequences of cocaine-mediated immunoregulation using a murine model of lung cancer. 3) We will investigate the effects of cocaine on the pathogenesis of AIDS by assessing: (a) its effect on infectivity and replication of HIV in vitro (in human Ams obtained at bronchoscopy) and in vivo (using the SCID mouse) and (b) its effect on the antimicrobial function of HIV-infected AMs., findings which relate to susceptibility to opportunistic infections in HIV-infected cocaine smokers.